PROJECT SUMMARY The transport of molecules in and out of the nucleus is an essential cellular process that occurs through multiprotein channels called nuclear pore complexes (NPCs). By controlling the exchange of proteins and RNAs across the nuclear envelope, NPCs have an indirect control of gene regulation that strongly impacts many processes including cell growth and proliferation. NPCs also regulate chromatin organization, DNA repair and DNA replication and, thus, play an important function in the maintenance of genome integrity. Having such critical roles in cellular homeostasis it is not surprising that many cancer cells show alterations in NPCs and their components. But, even though abnormalities in NPCs have long been observed cancer cells, how this these alterations affect nuclear pore function and whether they contribute to malignant transformation is mostly unknown. Understanding how alterations in NPCs affect cellular function is a critical step towards establishing how changes in the nuclear transport machinery are exploited to favor malignant transformation. Our previous work uncovered that the tissue-specific NPC component Nup210 acts as an anti-apoptotic factor in specific cell types, including muscle cells, neurons and T lymphocytes. We have identified that several leukemias show an up-regulation of this tissue-specific NPC component, and that Nup210 is important for leukemic transformation. We hypothesize that increased levels of Nup210 provide transformed hematopoietic cells with a survival advantage that contributes to leukemogenesis. In this proposal we seek to uncover how Nup210 promotes cell survival and leukemic transformation by characterizing its role in the regulation of leukemia cell metabolism (Aim1), and by establishing the signaling/survival pathways regulated by Nup210 in these cells (Aim 2). Besides offering a novel perspective on nuclear pore complex function and providing evidence on the molecular mechanisms exploited by these structures to promote cancer cell survival, we expect our work will result in the identification of specific differences between the nuclear transport machinery of normal and cancer cells that could lead to the development of new anti-cancer therapies.